The Iwagaki oyster Crassostrea nippona is an important aquaculture species with significant potential for large-scale oyster farming. It is susceptible to the fluctuated salinity in the coastal area. In this study, we compared the transcriptome of Crassostrea nippona larvae under variant conditions with low-salinity stress (28, 20, 15, 10, and 5 practical salinity units (psu)) for 24 h. KEGG enrichment analysis of differentially expressed genes (DEGs) from pairwise comparisons identified several free amino acid metabolism pathway (taurine and hypotaurine, arginine and proline, glycine, and beta-alanine) contributing to the salinity change adaptation and activated “lysosome” and “apoptosis” pathway in response to the low-salinity stress (10 and 5 psu). Trend analysis revealed sustained upregulation of transmembrane transport–related genes (such as SLC family) and downregulation of ribosomal protein synthesis genes faced with decreasing salinities. In addition, 9 biomarkers in response to low-salinity stress were identified through weighted gene co-expression network analysis (WGCNA) and validated by qRT-PCR. Our transcriptome analysis provides a comprehensive view of the molecular mechanisms and regulatory networks underlying the adaptive responses of oyster larvae to hypo-salinity conditions. These findings contribute to our understanding of the complex biological processes involved in oyster resilience and adaptation to changing environmental conditions.